1. Field of the Invention
The present invention is directed to methods of preparing carbocyclic compounds and intermediates therefore.
2. Brief Description of Related Art
U.S. patent application Ser. No. 08/702,308, filed Aug. 23, 1996, which was a continuation-in-part application of U.S. patent application Ser. No. 08/653,034, filed Mar. 24, 1996, which was a continuation-in-part application of U.S. patent application Ser. No. 08/606,624, filed Feb. 26, 1996, which was a continuation-in-part application of U.S. patent application Ser. No. 08/580,567, filed Dec. 29, 1995, which was a continuation-in-part application of U.S. patent application Ser. No. 08/476,946, filed Jun. 6, 1995, which was a continuation-in-part application of U.S. patent application Ser. No. 08/395,245, filed Feb. 27, 1995, all of which are incorporated herein by reference in their entirety, describe, inter alia, neuraminadase inhibitors and intermediates in the synthesis of neuraminidase inhibitor. The present invention provides processes useful in the preparation of these compositions.
Selected embodiments of the invention are directed to one or more of the following objects:
A principal object of the invention is to provide new synthetic methods and compositions.
An additional object of the invention is to provide new methods of preparing intermediates useful in the synthesis of neuraminidase inhibitors.
An additional object of the invention is to provide compositions useful as intermediates that are themselves useful in the synthesis of neuraminidase inhibitors.
An additional object of the invention is to provide compositions useful as neuraminidase inhibitors.
One aspect of the present invention is directed to processes for the preparation of compounds of the formula: 
wherein:
R1 is a cyclic hydroxy protecting group;
R2 is a carboxylic acid protecting group;
R3 is a hydroxy protecting group; and
each R20 is independently H or an alkyl of 1 to 12 carbon atoms;
which process comprises reaction of a compound of the formula: 
with a dehydrating reagent.
Another aspect of the present invention is directed to processes for the preparation of compounds of the formula: 
wherein:
each of R2, R3 and R20 are as defined above;
R4 is xe2x80x94C(R30)3;
each R5 is independently H or R3;
each R7 is independently H or an amino protecting group;
each R8 is independently H or R2;
each R9 is independently H or a thiol protecting group;
each R21 is independently R20, Br, Cl, F, I, CN, NO2 or N3;
each R22 is independently F, Cl, Br, I, xe2x80x94CN, N3, xe2x80x94NO2, xe2x80x94OR5, xe2x80x94OR20, xe2x80x94N(R20)2, xe2x80x94N(R20)(R7), xe2x80x94N(R7)2, xe2x80x94SR20, xe2x80x94SR9, xe2x80x94S(O)R20, xe2x80x94S(O)2R20, xe2x80x94S(O)OR8, xe2x80x94S(O)2OR20, xe2x80x94S(O)2OR8, xe2x80x94C(O)OR20, xe2x80x94C(O)OR8, xe2x80x94OC(O)R20, xe2x80x94N(R20)(C(O)R20), xe2x80x94N(R7)(C(O)R20), xe2x80x94N(R20)(C(O)OR20), xe2x80x94N(R7)(C(O)OR20), xe2x80x94C(O)N(R20)2, xe2x80x94C(O)N(R7)(R20), xe2x80x94C(O)N(R7)2, xe2x80x94C(NR20)(N(R20)2), xe2x80x94C(N(R7))(N(R20)2), xe2x80x94C(N(R20))(N(R20)(R7)), xe2x80x94C(N(R7))(N(R20)(R7)), xe2x80x94C(N(R20))(N(R7)2), xe2x80x94C(N(R7))(N(R7)2), xe2x80x94N(R20)C(N(R20))(N(R20)2), xe2x80x94N(R20)C(N(R20))(N(R20)(R7)), xe2x80x94N(R20)C(N(R7))(N(R20)2), xe2x80x94N(R7)C(N(R20))(N(R20)2), xe2x80x94N(R7)C(N(R7))(N(R20)2), xe2x80x94N(R7)C(N(R20))(N(R20)(R7)), xe2x80x94N(R20)C(N(R7)(N(R20)(R7)), xe2x80x94N(R20)C(N(R20))(N(R7)2), xe2x80x94N(R7)C(N(R7))(N(R20)(R7)), xe2x80x94N(R7)C(N(R20))(N(R7)2), xe2x80x94N(R20)C(N(R7))(N(R7)2), xe2x80x94N(R7)C(N(R7))(N(R7)2), xe2x95x90O, xe2x95x90S, xe2x95x90N(R20), xe2x95x90N(R7) or W;
each R23 is independently alkyl of 1 to 11 carbon atoms, alkenyl of 2 to 11 carbon atoms, or alkynyl of 2 to 11 carbon atoms;
each R24 is independently R23 wherein each R23 is substituted with 0 to 3 R22 groups;
each R24a is independently alkylene of 1 to 11 carbon atoms, alkenylene of 2 to 11 carbon atoms, or alkynylene of 2-11 carbon atoms any one of which alkylene, alkenylene or alkynylene is substituted with 0-3 R22 groups;
each R28 is independently alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, or alkynyl of 2 to 12 carbon atoms;
each R29 is independently R22 or R28 wherein each R28 is substituted with 0 to 3 R22 groups;
each R30 is independently H, R24, W or xe2x80x94R24aW; and
each W is independently carbocycle or heterocycle wherein any one of which carbocycle or heterocycle is substituted with 0 to 3 R29 groups;
which process comprises reaction of a compound of the formula: 
wherein R31 is a ketal or acetal, with a lewis acid reagent; provided-that R4, taken as a whole, contains:
0 to 3 W groups substituted with 0 to 3 R29 groups; and, in addition,
1 to 12 carbon atoms substituted with 0 to 3 R22 groups.
Another aspect of the present invention is directed to processes for the preparation of compounds of the formula: 
wherein:
R2, R4, R7, R20 and R21 are as defined above.
which process comprises reaction of a compound of the formula: 
with a reducing reagent.
Another aspect of the present invention is directed to processes for the preparation of compounds of the formula: 
wherein:
R2, R4, R5, R20 and R21 are as described above; and
Y1 is a mono-, di- or unsubstituted amino group;
which process comprises reaction of a compound of the formula: 
with an amine reagent.
Another aspect of the present invention is directed to processes for the preparation of compounds of the formula: 
wherein:
R2, R4, R20, R21 and Y1 are as described above;
which process comprises reaction of a compound of the formula: 
with an oxidizing reagent.
Another aspect of the present invention is directed to processes for the preparation of compounds of the formula: 
wherein:
R2, R4, R20, R21 and Y1 are as described above;
which process comprises reaction of a compound of the formula: 
with a base.
Another aspect of the present invention is directed to processes for the preparation of compounds of the formula: 
wherein:
R2, R4, R7, R20, R21 and Y1 are as described above;
which process comprises reaction of a compound of the formula: 
with a reductive amination reagent.
General
The present invention is directed to methods of making the compositions described herein. Even though the compositions of the invention are prepared by any of the applicable techniques of organic synthesis, the present invention provides advantageous methods for accomplishing the preparations.
Many conventional techniques are well known in the art and will not be elaborated here. However, many of the known techniques are elaborated in xe2x80x9cCompendium of Organic Synthetic Methodsxe2x80x9d (John Wiley and Sons, New York), Vol. 1, Ian T. Harrison and Shuyen Harrison, 1971; Vol. 2, Ian T. Harrison and Shuyen Harrison, 1974; Vol. 3, Louis S. Hegedus and Leroy Wade, 1977; Vol. 4, Leroy G. Wade, jr., 1980; Vol. 5, Leroy G. Wade, Jr., 1984; and Vol. 6, Michael B. Smith; as well as March, J., xe2x80x9cAdvanced Organic Chemistry, Third Editionxe2x80x9d, (John Wiley and Sons, New York, 1985), xe2x80x9cComprehensive Organic Synthesis. Selectivity, Strategy and Efficiency in Modern Organic Chemistry. In 9 Volumesxe2x80x9d, Barry M. Trost, Editor-in-Chief (Pergamon Press, New York, 1993 printing).
Generally, the reaction conditions such as temperature, reaction time, solvents, workup procedures, and the like, will be those common in the art for the particular reaction to be performed. The cited reference material, together with material cited therein, contains detailed descriptions of such conditions.
The terms xe2x80x9ctreatedxe2x80x9d, xe2x80x9ctreatingxe2x80x9d, xe2x80x9ctreatmentxe2x80x9d, and the like, mean contacting, mixing, reacting, allowing to react, bringing into contact, and other terms common in the art for indicating that one or more chemical entities is treated in such a manner as to convert it to one or more other chemical entities. This means that xe2x80x9ctreating compound one with compound twoxe2x80x9d is synonymous with xe2x80x9callowing compound one to react with compound twoxe2x80x9d, xe2x80x9ccontacting compound one with compound twoxe2x80x9d, xe2x80x9creacting compound one with compound twoxe2x80x9d, and other expressions common in the art of organic synthesis for reasonably indicating that compound one was xe2x80x9ctreatedxe2x80x9d, xe2x80x9creactedxe2x80x9d, xe2x80x9callowed to reactxe2x80x9d, etc., with compound two.
xe2x80x9cTreatingxe2x80x9d indicates the reasonable and usual manner in which organic chemicals are allowed to react. Normal concentrations (0.01M to 10M, typically 0.1M to 1M), temperatures (xe2x88x92100xc2x0 C. to 250xc2x0 C., typically xe2x88x9278xc2x0 C. to 150xc2x0 C., more typically xe2x88x9278xc2x0 C. to 100xc2x0 C., still more typically 0xc2x0 C. to 100xc2x0 C.), solvents (aprotic or protic), reaction times (typically 10 seconds to 10 days, more typically 1 min. to 10 hours, still more typically 10 min. to 6 hours), reaction vessels (typically glass, plastic, metal), pressures, atmospheres (typically air for oxygen and water insensitive reactions or nitrogen or argon for oxygen or water sensitive), etc., are intended unless otherwise indicated. The knowledge of similar reactions known in the art of organic synthesis are used in selecting the conditions and apparatus for xe2x80x9ctreatingxe2x80x9d in a given process. In particular, one of ordinary skill in the art of organic sysnthesis selects conditions and apparatus reasonably expected to successfully carry out the chemical reactions of the described processes based on the knowledge in the art.
Oxidation and reduction reactions are typically carried out at temperatures near room temperature (about 20xc2x0 C.), although for metal hydride reductions frequently the temperature is reduced to 0xc2x0 C. to xe2x88x92100xc2x0 C., solvents are typically aprotic for reductions and may be either protic or aprotic for oxidations. Reaction times are adjusted to achieve desired conversions.
Condensation reactions are typically carried out at temperatures near room temperature, although for non-equilibrating, kinetically controlled condensations reduced temperatures (0xc2x0 C. to xe2x88x92100xc2x0 C.) are also common. Solvents can be either protic (common in equilibrating reactions) or aprotic (common in kinetically controlled reactions).
Standard synthetic techniques such as azeotropic removal of reaction by-products and use of anhydrous reaction conditions (e.g. inert gas environments) are common in the art and will be applied when applicable. Workup typically consists of quenching any unreacted reagents followed by partition between a water/organic layer system (extraction) and separating the layer containing the product. Each of the products of the following processes is optionally separated, isolated, and/or purified prior to its use in subsequent processes.
Embodiments
One aspect of the present invention is directed to processes for the preparation of compounds of the formula: 
R1 is a cyclic hydroxy protecting group. A very large number of common protecting groups (including cyclic hydroxy protecting groups) and corresponding chemical cleavage reactions are described in xe2x80x9cProtective Groups in Organic Chemistryxe2x80x9d, Theodora W. Greene (John Wiley and Sons, Inc., New York, 1991, ISBN 0-471-62301-6) (xe2x80x9cGreenexe2x80x9d). See also Kocienski, Philip J.; xe2x80x9cProtecting Groupsxe2x80x9d (Georg Thieme Verlag Stuttgart, New York, 1994). In particular Chapter 1, Protecting Groups: An Overview, pages 1-20, Chapter 2, Hydroxyl Protecting Groups, pages 21-94, Chapter 3, Diol Protecting Groups, pages 95-117, Chapter 4, Carboxyl Protecting Groups, pages 118-154, Chapter 5, Carbonyl Protecting Groups, pages 155-184, and Chapter 6, Amino Protecting Groups, pages 185-243. Typically, the cyclic hydroxyprotecting groups are those commonly useful as 1,2-diol protecting groups.
Typical 1,2-diol protecting groups (thus, generally where two OH groups are taken together with the R1 protecting functionality) are described in Greene at pages 118-142 and include Cyclic Acetals and Ketals (Methylene, Ethylidene, 1-t-Butylethylidene, 1-Phenylethylidene, (4-Methoxyphenyl)ethylidene, 2,2,2-Trichloroethylidene, Acetonide (Isopropylidene), Cyclopentylidene, Cyclohexylidene, Cycloheptylidene, Benzylidene, p-Methoxybenzylidene, 2,4-Dim ethoxybenzylidene, 3,4-Dimethoxybenzylidene, 2-Nitrobenzylidene); Cyclic Ortho Esters (Methoxymethylene, Ethoxymethylene, Dimethoxymethylene, 1-Methoxyethylidene, 1-Ethoxyethylidine, 1,2-Dimethoxyethylidene, xcex1-Methoxybenzylidene, 1-(N,N-Dimethylamino)ethylidene Derivative, xcex1-(N,N-Dimethylamino)benzylidene Derivative, 2-Oxacyclopentylidene); Silyl Derivatives (Di-t-butylsilylene Group, 1,3-(1,1,3,3-Tetraisopropyldisiloxanylidene), and Tetra-t-butoxydisiloxane-1,3-diylidene), Cyclic Carbonates, Cyclic Boronates, Ethyl Boronate and Phenyl Boronate.
More typically, 1,2-diol protecting groups include those shown in Table A, or ayalic ketals or acetals. Still more typically, cyclic ketals and acetals.
wherein R1a is C1-C6 alkyl (as defined immediately below).
xe2x80x9cAlkylxe2x80x9d as used herein, unless stated to the contrary, is C1-C6 hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms. Examples are methyl (Me, xe2x80x94CH3), ethyl (Et, xe2x80x94CH2CH3), 1-propyl (n-Pr, n-propyl, xe2x80x94CH2CH2CH3), 2-propyl (i-Pr, i-propyl, xe2x80x94CH(CH3)2), 1-butyl (n-Bu, n-butyl, xe2x80x94CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-butyl, xe2x80x94CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, xe2x80x94CH(CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, xe2x80x94C(CH3)3), 1-pentyl (n-pentyl, xe2x80x94CH2CH2CH2CH2CH3), 2-pentyl (xe2x80x94CH(CH3)CH2CH2CH3), 3-pentyl (xe2x80x94CH(CH2CH3)2), 2-methyl-2-butyl (xe2x80x94C(CH3)2CH2CH3), 3-methyl-2-butyl (xe2x80x94CH(CH3)CH(CH3)2), 3-methyl-1-butyl (xe2x80x94CH2CH2CH(CH3)2), 2-methyl-1-butyl (xe2x80x94CH2CH(CH3)CH2CH3), 1-hexyl (xe2x80x94CH2CH2CH2CH2CH2CH3), 2-hexyl (xe2x80x94CH(CH3)CH2CH2CH2CH3), 3-hexyl (CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (xe2x80x94C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (xe2x80x94CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (xe2x80x94CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (xe2x80x94C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (xe2x80x94CH(CH3)C(CH3)3). Typical alkyls are methyl, ethyl, 1-propyl, and 2-propyl.
R2 is a carboxylic acid protecting group. Typical carboxylic acid protecting groups are R25 (described immediately below) or those described in Greene at pages 224-276. Those described in Greene include Esters (Methyl); Substituted Methyl Esters (9-Fluorenylmethyl, Methoxymethyl, Methylthiomethyl, Tetrahydropyranyl, Tetrahydrofuranyl, Methoxyethoxymethyl, 2-(Trimethylsilyl)ethoxymethyl, Benzyloxymethyl, Phenacyl, p-Bromophenacyl, xcex1-Methylphenacyl, p-Methoxyphenacyl, Carboxamidomethyl, N-Phthalimidomethyl); 2-Substituted Ethyl Esters (2,2,2-Trichloroethyl, 2-Haloethyl, xcfx89-Chloroalkyl, 2-(Trimethylsilyl)ethyl, 2-Methylthioethyl, 1,3-Dithianyl-2-methyl, 2-(p-Nitrophenylsulfenyl)ethyl, 2-(p-Toluenesulfonyl)ethyl, 2-(2xe2x80x2-Pyridyl)ethyl, 2-(Diphenylphosphino)ethyl, 1-Methyl-1-phenylethyl, t-Butyl, Cyclopentyl, Cyclohexyl, Allyl, 3-Buten-1-yl, 4-(Trimethylsilyl)-2-buten-1-yl, Cinnamyl, xcex1-Methylcinnamyl, Phenyl, p-(Methylmercapto)phenyl, Benzyl); Substituted Benzyl Esters (Triphenylmethyl, Diphenylmethyl, Bis(o-nitrophenyl)methyl, 9-Anthrylmethyl, 2-(9,10-Dioxo)anthrylmethyl, 5-Dibenzosuberyl, 1-Pyrenylmethyl, 2-(Trifluoromethyl)-6-chromylmethyl, 2,4,6-Trimethylbenzyl, p-Bromobenzyl, o-Nitrobenzyl, p-Nitrobenzyl, p-Methoxybenzyl, 2,6-Dimethoxybenzyl, 4-(Methylsulfinyl)benzyl, 4-Sulfobenzyl, Piperonyl, 4-Picolyl, p-poly-Benzyl); Silyl Esters (Trimethylsilyl, Triethylsilyl, t-Butyldimethylsilyl, i-Propyldimethylsilyl, Phenyldimethylsilyl, Di-t-butylmethylsilyl); Activated Esters (Thiols); Miscellaneous Derivatives (Oxazoles, 2-Alkyl-1,3-oxazolines, 4-Alkyl-5-oxo-1,3-oxazolidines, 5-Alkyl4-oxo-1,3-dioxolanes, Ortho Esters, Phenyl Group, Pentaaminocobalt(III) Complex); Stannyl Esters (Triethylstannyl, Tri-n-butylstannyl); Amides (N,N-Dimethyl, Pyrrolidinyl, Piperidinyl, 5,6-Dihydrophenanthridinyl, o-Nitroanilides, N-7-Nitroindolyl, N-8-Nitro-1,2,3,4-tetrahydroquinolyl, p-poly-Benzenesulfonamides); and Hydrazides (Hydrazides, N-Phenyl, N,Nxe2x80x2-Diisopropyl).
R25 is alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, or alkynyl of 2 to 12 carbon atoms, any one of which alkyl, alkenyl, or alkynyl is substituted with 0-3 R22 groups (R22 is described below). More typically R25 is alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, or alkynyl of 2 to 6 carbon atoms, any one of which alkyl, alkenyl, or alkynyl is substituted with 0-3 R22 groups. Still more typically, R25 is alkyl of 1 to 8 carbon atoms substituted with 0-2 R22 groups. Even more typically, R25 is alkyl of 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms. Most typically R25 is methyl, ethyl, 1-propyl or 2-propyl.
xe2x80x9cAlkenylxe2x80x9d as used herein, unless stated to the contrary, is C1-C6 hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms. Examples are ethenyl (xe2x80x94CHxe2x95x90CH2), 1-prop-1-enyl (xe2x80x94CHxe2x95x90CHCH3), 1-prop-2-enyl (xe2x80x94CH2CHxe2x95x90CH2), 2-prop-1-enyl (xe2x80x94C(xe2x95x90CH2)(CH3)), 1-but-1-enyl (xe2x80x94CHxe2x95x90CHCH2CH3), 1-but-2-enyl (xe2x80x94CH2CHxe2x95x90CHCH3), 1-but-3-enyl (xe2x80x94CH2CH2CHxe2x95x90CH2), 2-methyl-1-prop-1-enyl (xe2x80x94CHxe2x95x90C(CH3)2), 2-methyl-1-prop-2-enyl (xe2x80x94CH2C(xe2x95x90CH2)(CH3)), 2-but-1-enyl (xe2x80x94C(xe2x95x90CH2)CH2CH3), 2-but-2-enyl (xe2x80x94C(CH3)xe2x95x90CHCH3), 2-but-3-enyl (xe2x80x94CH(CH3)CHxe2x95x90CH2), 1-pent-1-enyl (xe2x80x94Cxe2x95x90CHCH2CH2CH3), 1-pent-2-enyl (xe2x80x94CHCHxe2x95x90CHCH2CH3), 1-pent-3-enyl (xe2x80x94CHCH2CHxe2x95x90CHCH3), 1-pent-4-enyl (xe2x80x94CHCH2CH2CHxe2x95x90CH2), 2-pent-1-enyl (xe2x80x94C(xe2x95x90CH2)CH2CH2CH3), 2-pent-2-enyl (xe2x80x94C(CH3)xe2x95x90CH2CH2C ), 2-pent-3-enyl (xe2x80x94CH(CH3)CHxe2x95x90CHCH3), 2-pent-4-enyl (xe2x80x94CH(CH3)CH2CHxe2x95x90CH2) or 3-methyl-1-but-2-enyl (CH2CHxe2x95x90C(CH3)2). More typically, alkenyl groups are of 2, 3 or 4 carbon atoms.
xe2x80x9cAlkynylxe2x80x9d as used herein, unless stated to the contrary, is C1-C6 hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms. Examples are ethynyl (xe2x80x94Cxe2x89xa1H), 1-prop-1-ynyl (xe2x80x94Cxe2x89xa1CCH3), 1-prop-2-ynyl (CH2Cxe2x89xa1CH), 1-but-1-ynyl (xe2x80x94Cxe2x89xa1CH2CH3), 1-but-2-ynyl (xe2x80x94CH2Cxe2x89xa1CCH3), 1-but-3-ynyl (xe2x80x94CH2CH2Cxe2x89xa1CH), 2-but-3-ynyl (CH(CH3)Cxe2x95x90CH), 1-pent-1-ynyl (xe2x80x94Cxe2x95x90CCH2CH2CH3), 1-pent-2-ynyl (xe2x80x94CH2Cxe2x95x90CCH2CH3), 1-pent-3-ynyl (xe2x80x94CH2CH2Cxe2x89xa1CCH3) or 1-pent-4-ynyl (xe2x80x94CH2CH2CH2Cxe2x89xa1CH). More typically, alkynyl groups are of 2, 3 or 4 carbon atoms.
R3 is a hydroxy protecting group. Typical R3 hydroxy protecting groups described in Greene (pages 14-118) include Ethers (Methyl); Substituted Methyl Ethers (Methoxymethyl, Methylthiomethyl, t-Butylthiomethyl, (Phenyldimethylsilyl)methoxymethyl, Benzyloxymethyl, p-Methoxybenzyloxymethyl, (4-Methoxyphenoxy)methyl, Guaiacolmethyl, t-Butoxymethyl, 4-Pentenyloxymethyl, Siloxymethyl, 2-Methoxyethoxymethyl, 2,2,2-Trichloroethoxymethyl, Bis(2-chloroethoxy)methyl, 2-(Trimethylsilyl)ethoxymethyl, Tetrahydropyranyl, 3-Bromotetrahydropyranyl, Tetrahydropthiopyranyl, 1-Methoxycyclohexyl, 4-Methoxytetrahydropyranyl, 4-Methoxytetrahydrothiopyranyl, 4-Methoxytetrahydropthiopyranyl S,S-Dioxido, 1-[(2-Chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl, 35, 1,4-Dioxan-2-yl, Tetrahydrofuranyl, Tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-Octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl)); Substituted Ethyl Ethers (1-Ethoxyethyl, 1-(2-Chloroethoxy)ethyl, 1-Methyl-1-methoxyethyl, 1-Methyl-1-benzyloxyethyl, 1-Methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-Trichloroethyl, 2-Trimethylsilylethyl, 2-(Phenylselenyl)ethyl, t-Butyl, Allyl, p-Chlorophenyl, p-Methoxyphenyl, 2,4-Dinitrophenyl, Benzyl); Substituted Benzyl Ethers (p-Methoxybenzyl, 3,4-Dimethoxybenzyl, o-Nitrobenzyl, p-Nitrobenzyl, p-Halobenzyl, 2,6-Dichlorobenzyl, p-Cyanobenzyl, p-Phenylbenzyl, 2- and 4-Picolyl, 3-Methyl-2-picolyl N-Oxido, Diphenylmethyl, p,pxe2x80x2-Dinitrobenzhydryl, 5-Dibenzosuberyl, Triphenylmethyl, xcex1-Naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, Di(p-methoxyphenyl)phenylmethyl, Tri(p-methoxyphenyl)methyl, 4-(4xe2x80x2-Bromophenacyloxy)phenyldiphenylmethyl, 4,4xe2x80x2,4xe2x80x3-Tris(4,5-dichlorophthalimidophenyl)methyl, 4,4xe2x80x2,4xe2x80x3-Tris(levulinoyloxyphenyl)methyl, 4,4xe2x80x2,4xe2x80x3-Tris(benzoyloxyphenyl)methyl, 3-(Imidazol-1-ylmethyl)bis(4xe2x80x2,4xe2x80x3-dimethoxyphenyl)methyl, 1,1-Bis(4-methoxyphenyl)-1xe2x80x2-pyrenylmethyl, 9-Anthryl, 9-(9-Phenyl)xanthenyl, 9-(9-Phenyl-10-oxo)anthryl, 1,3-Benzodithiolan-2-yl, Benzisothiazolyl S,S-Dioxido); Silyl Ethers (Trimethylsilyl, Triethylsilyl, Triisopropylsilyl, Dimethylisopropylsilyl, Diethylisopropylsily, Dimethylthexylsilyl, t-Butyldimethylsilyl, t-Butyldiphenylsilyl, Tribenzylsilyl, Tri-p-xylylsilyl, Triphenylsilyl, Diphenylmethylsilyl, t-Butylmethoxyphenylsilyl); Esters (Formate, Benzoylformate, Acetate, Choroacetate, Dichloroacetate, Trichloroacetate, Trifluoroacetate, Methoxyacetate, Triphenylmethoxyacetate, Phenoxyacetate, p-Chlorophenoxyacetate, p-poly-Phenylacetate, 3-Phenylpropionate, 4-Oxopentanoate (Levulinate), 4,4-(Ethylenedithio)pentanoate, Pivaloate, Adamantoate, Crotonate, 4-Methoxycrotonate, Benzoate, p-Phenylbenzoate, 2,4,6-Trimethylbenzoate (Mesitoate)); Carbonates (Methyl, 9-Fluorenylmethyl, Ethyl, 2,2,2-Trichloroethyl, 2-(Trimethylsilyl)ethyl, 2-(Phenylsulfonyl)et-hyl, 2-(Triphenylphosphonio)ethyl, Isobutyl, Vinyl, Allyl, p-Nitrophenyl, Benzyl, p-Methoxybenzyl, 3,4-Dimethoxybenzyl, o-Nitrobenzyl, p-Nitrobenzyl, S-Benzyl Thiocarbonate, 4-Ethoxy-1-naphthyl, Methyl Dithiocarbonate); Groups With Assisted Cleavage (2-lodobenzoate, 4-Azidobutyrate, 4-Niotro-4-methylpentanoate, o-(Dibromomethyl)benzoate, 2-Formylbenzenesulfonate, 2-(Methylthiomethoxy)ethyl Carbonate, 4-(Methylthiomethoxy)butyrate, 2-(Methylthiomethoxymethyl)benzoate); Miscellaneous Esters (2,6-Dichloro-4-methylphenoxyacetate, 2,6-Dichloro-4-(1,1,3,3 tetramethylbutyl)phenoxyacetate, 2,4-Bis(1,1-dimethylpropyl)phenoxyacetate, Chorodiphenylacetate, Isobutyrate, Monosuccinoate, (E)-2-Methyl-2-butenoate (Tigloate), o-(Methoxycarbonyl)benzoate, p-poly-Benzoate, xcex1-Naphthoate, Nitrate, Alkyl N,N,Nxe2x80x2,Nxe2x80x2-Tetramethylphosphorodiamidate, N-Phenylcarbamate, Borate, Dimethylphosphinothioyl, 2,4-Dinitrophenylsulfenate); and Sulfonates (Sulfate, Methanesulfonate (Mesylate), Benzylsulfonate, Tosylate).
More typically, R3 hydroxy protecting groups include substituted methyl ethers, substituted benzyl ethers, silyl ethers, and esters including sulfonic acid esters, still more typically, trialkylsilyl ethers, tosylates, mesylates and acetates.
Each R20 is independently H or an alkyl of 1 to 12 carbon atoms. Typically R20 is H or alkyl of 1 to 6 carbon as described above. Still more typically, R20 is H or methyl. More typically yet, R20 is H.
This process embodiment comprises reaction of a compound of the formula: 
with a dehydrating reagent. Typically the hydroxy group at position 1 is eliminated without removing the cis-4,5-diol protecting group. The hydroxy group at position 1 is eliminated to form an olefinic bond between positions 1 and 6.
Typically the process comprises treating compound 4 with a suitable dehydrating agent, such as a mineral acid (HCl, H2SO4) or SO2Cl2. More typically, compound 4 is treated with SO2Cl2, followed by an alkanol. Still more typically, compound 4 is treated with SO2Cl2 in a suitable polar, aprotic solvent, such as an amine to form an olefin. More typically yet, compound 4 is treated with SO2Cl2 in pyridine/CH2Cl2 at a temperature between xe2x88x92100xc2x0 C. and 0xc2x0 C., typically xe2x88x92100xc2x0 C. and xe2x88x9210xc2x0 C., more typically xe2x88x9278xc2x0 C., to form compound 5.
In a typical embodiment, a solution of compound 4 and pyridine in dichloromethane is cooled to xe2x88x9220xc2x0 to xe2x88x9230xc2x0 C. and treated portionwise with sulfuryl chloride. After the exothermic reation subsided, the resulting slurry is quenched with ethanol, warmed to 0xc2x0 C., and washed successively with 16% sulfuric acid, water and 5% aqueous sodium bicarbonate. A detailed example of this embodiment is provided as Example 4 below.
Optionally, the process of this embodiment further comprises purifying or separating compound 5 from any other reaction products or other contaminents such as other double bond isomers, halogenated side products or starting materials and reagents by treatment with a noble metal complex. Noble metals include gold, silver, platinum, palladium, iridium, rhenium, mercury, ruthenium and osmium. Typically, the noble metal complex of this embodiment is a complex of platinum or palladium. More typically the complex is a palladium (0) complex, still more typically, the complex is a tetrakis(triarylphosphine)palladium (0) complex.
In a typical embodiment the organic layer of the reaction contains a mixture of olefin and halogenated products as well as starting material. It is concentrated in vacuo and ethyl acetate is added. The solution is treated with pyrrolidine and tetrakis(triphenylphosphine)palladium(0) at ambient temperature, followed by washing with 16% sulfuric acid. The organic layer is filtered through a pad of silica gel and eluted with ethyl acetate. The filtrate is concentrated in vacuo. The residue is dissolved in ethyl acetate at reflux and hexane is added. Upon cooling, the product crystallizes and is separated by filtration and washed with 14% ethyl acetate in hexane. After drying in vacuo, 5 was obtained. A detailed example of this embodiment is provided as Example 4 below.
In another example of this embodiment compound 5 is of the formula: 
Another aspect of the present invention is directed to processes for the preparation of compounds of the formula: 
wherein:
R2, R3 and R20 are as defined above.
R4 is described below.
W is carbocycle or heterocycle wherein any one of which carbocycle or heterocycle is substituted with 0 to 3 R29 groups (R29 is described below).
W is a carbocycle or heterocycle, with the proviso that each W is independently substituted with 0 to 3 R29 groups (R29 is described below). W carbocycles and heterocycles are stable chemical structures. Such structures are isolatable in measurable yield, with measurable purity, from reaction mixtures at temperatures from xe2x88x9278xc2x0 C. to 200xc2x0 C. Each W is independently substituted with 0 to 3 R29 groups. Typically, W is a saturated, unsaturated or aromatic ring comprising a mono- or bicyclic carbocycle or heterocycle. More typically, W has 3 to 10 ring atoms, still more typically, 3 to 7 ring atoms, and ordinarily 3 to 6 ring atoms. The W rings are saturated when containing 3 ring atoms, saturated or monounsaturated when containing 4 ring atoms, saturated, or mono- or diunsaturated when containing 5 ring atoms, and saturated, mono- or diunsaturated, or aromatic when containing 6 ring atoms.
When W is carbocyclic, it is typically a 3 to 7 carbon monocycle or a 7 to 12 carbon atom bicycle. More typically, W monocyclic carbocycles have 3 to 6 ring atoms, still more typically 5 or 6 ring atoms. W bicyclic carbocycles typically have 7 to 12 ring atoms arranged as a bicyclo [4,5], [5,5], [5,6] or [6,6] system, still more typically, 9 or 10 ring atoms arranged as a bicydo [5,6] or [6,6] system. Examples include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cydohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, phenyl, spiryl and naphthyl.
A W heterocycle is typically a monocycle having 3 to 7 ring members (2 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S) or a bicycle having 7 to 10 ring members (4 to 9 carbon atoms and 1 to 3 heteroatoms selected from N, O,P, and S). More typically, W heterocyclic monocycles have 3 to 6 ring atoms (2 to 5 carbon atoms and 1 to 2 heteroatoms selected from N, O,and S), still more typically, 5 or 6 ring atoms (3 to 5 carbon atoms and 1 to 2 heteroatoms selected from N and S). W heterocyclic bicycles typically have 7 to 10 ring atoms (6 to 9 carbon atoms and 1 to 2 heteroatoms selected from N, O,and S) arranged as a bicyclo [4,5], [5,5], [5,6], or [6,6] system, still more typically, 9 to 10 ring atoms (8 to 9 carbon atoms and 1 to 2 hetero atoms selected from N and S) arranged as a bicyclo [5,6] or [6,6] system.
xe2x80x9cHeterocyclexe2x80x9d as used herein includes by way of example and not limitation these heterocycles described in Paquette, Leo A.; xe2x80x9cPrinciples of Modern Heterocyclic Chemistryxe2x80x9d (W. A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; xe2x80x9cThe Chemistry of Heterocyclic Compounds, A series of Monographsxe2x80x9d John Wiley and Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28; and xe2x80x9cJ. Am.
Chem. Soc.xe2x80x9d, 82:5566 (1960).
Examples of heterocycles include by way of example and not limitation pyridyl, thiazolyl, tetrahydrothiophenyl, sulfur oxidized tetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, 20 imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl, azocinyl, triazinyl, 6H-1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl, thienyl, thianthrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathiinyl, 2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, 1H-indazoly, purinyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, xcex2-carbolinyl, phenanthridinyl, acridinyl, pyrirnidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, and isatinoyl.
By way of example and not limitation, carbon bonded heterocycles are bonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or 6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position 2, 3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole, position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of an aziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6, 7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline. Still more typically, carbon bonded heterocycles include 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl.
By way of example and not limitation, nitrogen bonded heterocycles are bonded at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole, position 2 of a isoindole, or isoindoline, position 4 of a morpholine, and position 9 of a carbazole, or xcex2-carboline. Still more typically, nitrogen bonded heterocycles include 1-aziridyl, 1-azetedyl, 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl, and 1-piperidinyl.
Typically W heterocycles are selected from pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, s-triazinyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, furanyl, thiofuranyl, thienyl, or pyrrolyl.
More typically, the heterocycle of W is bonded through a carbon atom or nitrogen atom thereof. Still more typically W heterocycles are bonded by a stable covalent bond through a carbon or nitrogen atom thereof. Stable covalent bonds are chemically stable structures as described above.
W optionally is selected from the group consisting of: 
R5 is H or R3.
R7 is H or an amino protecting group. R7 amino protecting groups are described by Greene at pages 315-385. They include Carbamates (methyl and ethyl, 9-fluorenylmethyl, 9(2-sulfo)fluoroenylmethyl, 9-(2,7-dibromo)fluorenylmethyl, 2,7-di-t-buthyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl, 4-methoxyphenacyl); Substituted Ethyl (2,2,2-trichoroethyl, 2-trimethylsilylethyl, 2-phenylethyl, 1-(1-adamantyl)-1-methylethyl, 1,1-dimethyl-2-haloethyl, 1,1-dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl, 1-methyl-1-(4-biphenylyl)ethyl, 1-(3,5-di-t-butylphenyl)-1-methylethyl, 2-(2xe2x80x2- and 4xe2x80x2-pyridyl)ethyl, 2-(N,N-dicyclohexylcarboxamido)ethyl, t-butyl, 1-adamantyl, vinyl, allyl, 1-isopropylallyl, cinnamyl, 4-nitrocinnamyl, 8-quinolyl, N-hydroxypiperidinyl, alkyldithio, benzyl, p-methoxybenzyl, p-nitrobenzyl, p-bromobenzyl, p-chorobenzyl, 2,4-dichlorobenzyl, 4-methylsulfinylbenzyl, 9-anthrylmethyl, diphenylmethyl); Groups With Assisted Cleavage (2-methylthioethyl, 2-methylsulfonylethyl, 2-(p-toluenesulfonyl)ethyl, [2-(1,3-dithianyl)]methyl, 4-methylthiophenyl, 2,4-dimethylthiophenyl, 2-phosphonioethyl, 2-triphenylphosphonioisopropyl, 1,1-dimethyl-2-cyanoethyl, m-choro-p-acyloxybenzyl, p-(dihydroxyboryl)benzyl, 5-benzisoxazolylmethyl, 2-(trifluoromethyl)-6-chromonylmethyl); Groups Capable of Photolytic Cleavage (m-nitrophenyl, 3,5-dimethoxybenzyl, o-nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl, phenyl(o-nitrophenyl)methyl); Urea-Type Derivatives (phenothiazinyl-(10)-carbonyl, Nxe2x80x2-p-toluenesulfonylaminocarbonyl, Nxe2x80x2-phenylaminothiocarbonyl); Miscellaneous Carbamates (t-amyl, S-benzyl thiocarbamate, p-cyanobenzyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclopropylmethyl, p-decyloxybenzyl, diisopropylmethyl, 2,2-dimethoxycarbonylvinyl, o-(N,N-dimethylcarboxamido)benzyl, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl, 1,1-dimethylpropynyl, di(2-pyridyl)methyl, 2-furanylmethyl, 2-Iodoethyl, Isobornyl, Isobutyl, Isonicotinyl, p-(pxe2x80x2-Methoxyphenylazo)benzyl, 1-methylcyclobutyl, 1-methylcyclohexyl, 1-methyl-1-cyclopropylmethyl, 1-methyl-1-(3,5-dimethoxyphenyl)ethyl, 1-methyl-1-(p-phenylazophenyl)ethyl, 1-methyl-1-phenylethyl, 1-methyl-1-(4-pyridyl)ethyl, phenyl, p-(phenylazo)benzyl, 2,4,6-tri-t-butylphenyl, 4-(trimethylammonium)benzyl, 2,4,6-trimethylbenzyl); Amides (N-formyl, N-acetyl, N-choroacetyl, N-trichoroacetyl, N-trifluoroacetyl, N-phenylacetyl, N-3-phenylpropionyl, N-picolinoyl, N-3-pyridylcarboxamide, N-benzoylphenylalanyl, N-benzoyl, N-p-phenylbenzoyl); Amides With Assisted Cleavage (N-o-nitrophenylacetyl, N-o-nitrophenoxyacetyl, N-acetoacetyl, (Nxe2x80x2-dithiobenzyloxycarbonylamino)acetyl, N-3-(p-hydroxyphenyl)propionyl, N-3-(o-nitrophenyl)propionyl, N-2-methyl-2-(o-nitrophenoxy)propionyl, N-2-methyl-2-(o-phenylazophenoxy)propionyl, N-4-chlorobutyryl, N-3-methyl-3-nitrobutyryl, N-o-nitrocinnamoyl, N-acetylmethionine, N-o-nitrobenzoyl, N-o-(benzoyloxymethyl)benzoyl, 4,5-diphenyl-3-oxazolin-2-one); Cyclic Imide Derivatives (N-phthalimide, N-dithiasuccinoyl, N-2,3-diphenylmaleoyl, N-2,5-dimethylpyrrolyl, N-1,1,4,4-tetramethyldisilylazacyclopentane adduct, 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted 1,3-dibenzyl-1,3-5-triazacyclohexan-2-one, 1-substituted 3,5-dinitro4-pyridonyl); N-Alkyl and N-Aryl Amines (N-methyl, N-allyl, N-[2-(trimethylsilyl)ethoxy]methyl, N-3-acetoxypropyl, N-(1-isopropyl4-nitro-2-oxo-3-pyrrolin-3-yl), Quaternary Ammonium Salts, N-benzyl, N-di(4-methoxyphenyl)methyl, N-5-dibenzosuberyl, N-triphenylmethyl, N-(4-methoxyphenyl)diphenylmethyl, N-9-phenylfluorenyl, N-2,7-dichloro-9-fluorenylmethylene, N-ferrocenylmethyl, N-2-picolylamine Nxe2x80x2-oxide), Imine Derivatives (N-1,1-dimethylthiomethylene, N-benzylidene, N-p-me thoxybenylidene, N-diphenylmethylene, N-[(2-pyridyl)mesityl]methylene, N,(Nxe2x80x2,Nxe2x80x2-dimethylaminomethylene, N,Nxe2x80x2-isopropylidene, N-p-nitrobenzylidene, N-salicylidene, N-5-chlorosalicylidene, N-(5-chloro-2-hydroxyphenyl)phenylmethylene, N-cyclohexylidene); Enamine Derivatives (N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)); N-Metal Derivatives (N-borane derivatives, N-diphenylborinic acid derivatives, N-[phenyl(pentacarbonylchromium- or -tungsten)]carbenyl, N-copper or N-zinc chelate); N-N Derivatives (N-nitro, N-nitroso, N-oxide); N-P Derivatives (N-diphenylphosphinyl, N-dimethylthiophosphinyl, N-diphenylthiophosphinyl, N-dialkyl phosphoryl, N-dibenzyl phosphoryl, N-diphenyl phosphoryl); N-Si Derivatives; N-S Derivatives; N-Sulfenyl Derivatives (N-benzenesulfenyl, N-o-nitrobenzenesulfenyl, N-2,4-dinitrobenzenesulfenyl, N-pentachlorobenzenesulfenyl, N-2-nitro-4-methoxybenzenesulfenyl, N-triphenylmethylsulfenyl, N-3-nitropyridinesulfenyl); and N-sulfonyl Derivatives (N-p-toluenesulfonyl, N-benzenesulfonyl, N-2,3,6-trimethyl-4-methoxybenzenesulfonyl, N-2,4,6-trimethoxybenzenesulfonyl, N-2,6-dimethyl-4-methoxybenzenesulfonyl, N-pentamethylbenzenesulfonyl, N-2,3,5,6,-tetramethyl-4-methoxybenzenesulfonyl, N-4-methoxybenzenesulfonyl, N-2,4,6-trimethylbenzenesulfonyl, N-2,6-dimethoxy-4-methylbenzenesulfonyl, N-2,2,5,7,8-pentamethylchroman-6-sulfonyl, N-methanesulfonyl, N-xcex2-trimethylsilyethanesulfonyl, N-9-anthracenesulfonyl, N-4-(4xe2x80x2,8xe2x80x2-dimethoxynaphthylmethyl)benzenesulfonyl, N-benzylsulfonyl, N-trifluoromethylsulfonyl, N-phenacylsulfonyl). Typically, R7 is H or a xe2x80x94C(O)R25 (R25 is described above).
R8 is H or R2. Typically R8 is H.
R9 is H or a thiol protecting group. R9 amino protecting groups are described by Greene at pages 277-308. They includeThioethers (S-Benzyl, S-p-Methoxybenzyl, S-o- or p-Hydroxy- or Acetoxybenzyl, S-p-Nitrobenzyl, S-4-Picolyl, S-2-Picolyl N-Oxide, S-9-Anthrylmethyl, S-9-Fluorenylmethyl, S-Ferrocenylmethyl); S-Diphenylmethyl, Substituted S-Diphenylmethyl, and S-Triphenylmethyl Thioethers (S-Diphenylmethyl, S-Bis(4-methoxyphenyl)methyl, S-5-Dibenzosuberyl, S-Triphenylmethyl, S-Diphenyl-4-pyridylmethyl, S-Phenyl, S-2,4-Dinitrophenyl, S-t-Butyl, S-1-Adamantyl); Substituted S-Methyl Derivatives Monothio, Dithio, and Aminothio Acetals (S-Methoxymethyl, S-Isobutoxymethyl, S-2-Tetrahydropyranyl, S-Benzylthiomethyl, S-Phenylthiomethyl, Thiazolidines, S-Acetamidomethyl, S-Trimethylacetamidomethyl, S-Benzamidomethyl, S-Acetyl-, S-Carboxy-, and S-Cyanomethyl); Substituted S-Ethyl Derivatives (S-2-Nitro-1-phenylethyl, S-2-(4xe2x80x2-Pyridyl)ethyl, S-2-Cyanoethyl, S-2,2-Bis(carboethoxy)ethyl, S-1-m-Nitrophenyl-2-benzoylethyl, S-2-Phenylsulfonylethyl, S-1-(4-Methylphenylsulfonyl)-2-methylprop-2-yl); Silyl Thioethers, Thioesters, (S-Acetyl Derivative, S-Benzoyl Derivative, S-N-[[(p-Biphenylyl)isopropoxy]carbonyl]-N-methyl-xcex3-aminobutyrate, S-N-(t-Butoxycarbonyl)-N-methyl-xcex3-aminobutyrate); Thiocarbonate Derivatives (S-2,2,2-Trichloroethoxycarbonyl, S-t-Butoxycarbonyl, S-Benzyloxycarbonyl, S-p-Methoxybenzyloxycarbonyl); Thiocarbamate Derivatives (S-(N-Ethyl), S-(N-Methoxymethyl); Miscellaneous Derivatives, Unsymmetrical Disulfides (S-Ethyl, S-t-Butyl, Substituted S-Phenyl); Sulfenyl Derivatives (S-Sulfonate, S-Sulfenylthiocarbonate, S-3-Nitro-2-pyridinesulfenyl Sulfide); Protection for Dithiols, Dithio Acetals and Ketals (S,Sxe2x80x2-Methylene, S,Sxe2x80x2-Isopropylidene, and S,Sxe2x80x2-Benzylidene, S,Sxe2x80x2-p-Methoxybenzylidene); Protection for Sulfides (S-Methylsulfonium Salt, S-Benzyl- and S-4-Methoxybenzylsulfonium Salt, S-1-(4-Phthalimidobutyl)sulfonium Salt); S-P Derivatives (S-(Dimethylphosphino)thioyl, S-(Diphenylphosphino)thioyl);
Each R21 is independently R20, Br, Cl, F, I CN, NO2 or N3. Typically, R21 is Cl, F or R20, more typically, R20, still more typically, H.
Each R22 is independently F, Cl, Br, I, xe2x80x94CN, N3, xe2x80x94NO2, xe2x80x94OR5, xe2x80x94OR20, xe2x80x94N(R20)2, xe2x80x94N(R20)(R7), xe2x80x94N(R7)2, xe2x80x94SR20, xe2x80x94SR9, xe2x80x94S(O)R20, xe2x80x94S(O)2R20, xe2x80x94S(O)OR20, xe2x80x94S(O)OR8, xe2x80x94S(O)2OR20, xe2x80x94S(O)2OR8, C(O)OR20, xe2x80x94C(O)OR8, xe2x80x94OC(O)R20, xe2x80x94N(R20)(C(O)R20), xe2x80x94N(R7)(C(O)R20), xe2x80x94N(R20)(C(O)OR20), xe2x80x94N(R7)(C(O)OR20), xe2x80x94C(O)N(R20)2, xe2x80x94C(O)N(R7)(R20), xe2x80x94C(O)N(R7)2, xe2x80x94C(NR20)(N(R20)2), xe2x80x94C(N(R7))(N(R20)2), xe2x80x94C(N(R20))(N(R20)(R7)), xe2x80x94C(N(R7))(N(R20)(R7)), xe2x80x94C(N(R20))(N(R7)2), xe2x80x94C(N(R7))(N(R7)2), xe2x80x94N(R20)C(N(R20))(N(R20)2), xe2x80x94N(R20)C(N(R20))(N(R20)(R7)), xe2x80x94N(R20)C(N(R7))(N(R20)2), xe2x80x94N(R7)C(N(R20))(N(R20)2), xe2x80x94N(R7)C(N(R7))(N(R20)2), xe2x80x94N(R7)C(N(R20))(N(R20)(R7)), xe2x80x94N(R20)C(N(R7))(N(R20)(R7)), xe2x80x94N(R20)C(N(R20))(N(R7)2), xe2x80x94N(R7)C(N(R7))(N(R20)(R7)), xe2x80x94N(R7)C(N(R20))(N(R7)2), xe2x80x94N(R20)C(N(R7))(N(R7)2), xe2x80x94N(R7)C(N(R7))(N(R7)2), xe2x95x90O, xe2x95x90S, xe2x95x90N(R20), xe2x95x90N(R7) or W.
Typically R22 is F, Cl, Br, I, xe2x80x94CN, N3, xe2x80x94NO2, xe2x80x94OR5, xe2x80x94OR20, xe2x80x94N(R20)2, xe2x80x94N(R20)(R7), xe2x80x94N(R7)2, xe2x80x94SR20, xe2x80x94SR9, xe2x80x94S(O)R20, xe2x80x94S(O)2R20, xe2x80x94S(O)OR20, xe2x80x94S(O)OR8, xe2x80x94S(O)2OR20, xe2x80x94S(O)2OR8, xe2x80x94C(O)OR20, xe2x80x94C(O)OR8, xe2x95x90O, xe2x95x90S, xe2x95x90N(R20) or xe2x95x90N(R7). More typically R22 is F, Cl, Br, xe2x80x94CN, N3, xe2x80x94NO2, xe2x80x94OR5, xe2x80x94OR20, xe2x80x94N(R20)2, xe2x80x94N(R20)(R7), xe2x80x94N(R7)2, xe2x80x94C(O)OR20, xe2x80x94C(O)OR8,or xe2x95x90O. Still more typically R22 is F, Cl, Br, xe2x80x94CN, N3, xe2x80x94NO2, xe2x80x94OR20, xe2x80x94N(R20)2, xe2x80x94C(O)OR20 or xe2x95x90O. More typically yet R22 is F, Cl, Br, xe2x80x94CN, xe2x80x94OH, xe2x80x94N(H)2, (O)OR20 or xe2x95x90O.
Each R23 is independently alkyl of 1 to 11 carbon atoms, alkenyl of 2 to 11 carbon atoms, or alkynyl of 2 to 11 carbon atoms. More typically R23 is alkyl of 1 to 8 carbon atoms, alkenyl of 2 to 8 carbon atoms, or alkynyl of 2 to 8 carbon atoms, still more typically, R23 is alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, or alkynyl of 2 to 6 carbon atoms. More typically yet, R23 is R25.
Each R24 is independently R23 wherein each R23 is substituted with 0 to 3 R22 groups. Each of the typical embodiments of R23 and R22 are typical of R24. More typically R24 is substituted with 0, 1, 2, or 3 R22 groups.
R24a is independently alkylene of 1 to 11 carbon atoms, alkenylene of 2 to 11 carbon atoms, or alkynylene of 2-11 carbon atoms any one of which alkylene, alkenylene or alkynylene is substituted with 0-3 R22 groups. More typically R24a is alkylene of 1 to 8 carbon atoms, alkenylene of 2 to 8 carbon atoms, or alkynylene of 2 to 8 carbon atoms, still more typically, R24a is alkylene of 1 to 6 carbon atoms, alkenylene of 2 to 6 carbon atoms, or alkynylene of 2 to 6 carbon atoms. More typically yet, R24a is xe2x80x94CH2xe2x80x94, xe2x80x94CH2CH2xe2x80x94, xe2x80x94CH2CH2CH2xe2x80x94 or xe2x80x94C(H)(CH3)xe2x80x94.
Each R28 is independently alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, or alkynyl of 2 to 12 carbon atoms. More typically R28 is alkyl of 1 to 8 carbon atoms, alkenyl of 2 to 8 carbon atoms, or alkynyl of 2 to 8 carbon atoms, still more typically, R28 is alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, or alkynyl of 2 to 6 carbon atoms. More typically yet, R28 is R25.
Each R29 is independently R22 or R28 wherein each R28 is substituted with 0 to 3 R22 groups. Each of the typical embodiments of R28 and R22 are typical of R29. More typically R29 is substituted with 0, 1, 2, or 3 R22 groups.
Each R30 is independently H, R24, W or xe2x80x94R24aW.
R4 is xe2x80x94C(R30)3, provided that R4, taken as a whole, contains 0 to 1 W groups (W is described above) substituted with 0 to 3 R29 groups (R29 is described above); and, in addition, 1 to 12 carbon atoms substituted with 0 to 3 R22 groups (R22 is described above). Exemplary embodiments of R4 are provided as U1 embodiments in the documents cited in the xe2x80x9cBrief Description of Related Artxe2x80x9d above.
Typically one R30 is H. More typically, one R30 is H and the remaining two R30""s are independently R24, W or xe2x80x94R24aW. More typically yet, one R30 is H, one R30 is R24 and the remaining R30 is independently R24, W or xe2x80x94R24aW.
In one embodiment of R4, one R30 is H, one R30 is R25 and one R30 is R24, W or xe2x80x94R24aW. Typically, one R30 is H and two R30""s are R25. In another embodiment of R4, one R30 is H, one R30 is xe2x80x94R24aW and one R30 is R24, W or xe2x80x94R24aW. Typically, one R30 is H, one R30 is xe2x80x94R24aW and one R30 is R24. In another embodiment, one R30 is H and two R30""s are alkyl of 1 to 6 carbon atoms.
In another embodiment, R4 is: 
wherein R26 is H, xe2x80x94CH3, xe2x80x94CH2CH3, xe2x80x94CH2CH2CH3, xe2x80x94OCH3, xe2x80x94OAc (xe2x80x94Oxe2x80x94C(O)CH3), xe2x80x94OH, xe2x80x94NH2, or xe2x80x94SH, typically H, xe2x80x94CH3 or xe2x80x94CH2CH3.
Typically each R4 (taken as a whole) contains 0-3 W groups each of which is independently substituted with 0-3 R29 groups; and each R4 (taken as a whole) in addition contains 1-12 carbon atoms, each carbon atom of which is independently substituted with 0-3 R22 groups. More typically each R4 contains 0, 1 or 2 such W groups, more typically yet, 0 or 1 such W group.
In another embodiment, each R30 group (taken as whole) of R4 is not so electron withdrawing as to prevent the formation of compound 11. Lowry, T. H. and Richardson, K. S. xe2x80x9cMechanism and Theory in Organic Chemistryxe2x80x9d (Harper and Row, 1976) at section 2.2, pages 60-71, and March, J. xe2x80x9cAdvanced Organic Chemistryxe2x80x9d (McGraw-Hill, 1977) at Chapter 9, Quantitative Treatments of the Effect of Structure on Reactivityxe2x80x9d, pages 251-259, provide details of the electron withdrawing properties of substitutent groups. In another embodiment, each R30 group (taken as whole) of R4 has a Hammett "sgr"para value of less than about 1, typically less than about 0.75, more typically less than about 0.5. In another embodiment, each R30 group (taken as whole) of R4 has a Hammett "sgr"para value of xe2x88x921.0 to 1.0, more typically xe2x88x920.75 to 0.75, more typically yet xe2x88x920.5 to 0.5.
This process embodiment comprises reaction of a compound of the formula: 
wherein R31 is a ketal or acetal, with a lewis acid reagent. Typically R31 is xe2x80x94C(R30)2xe2x80x94 wherein R30 is as described above,
Typically, compound 10 is reacted with a Lewis acid catalyst common in the art, such as BF3.Et2O, TiCl3, TMSOTf, SmI2(THF)2, LiClO4, Mg(Cl4)2, Ln(OTf)3 (where Ln=Yb, Gd, Nd), Ti(Oixe2x80x94Pr)4, AlCl3, AlBr3, BeCl2, CdCl2, ZnCl2, BF3, BCl3, BBr3, GaCl3, GaBr3, TiCl4, TiBr4, ZrCl4, SnCl4, SnBr4, SbCl5, SbCl3, BiCl3, FeCl3, UCl4, ScCl3, YCl3, LaCl3, CeCl3, PrCl3, NdCl3, SmCl3, EuCl3, GdCl3, TbCl3, LuCl3, DYCl3, HoCl3, ErCl3, TmCl3, YbCl3, Znl2, Al(OPri)3, Al(acac)3, ZnBr2, or SnCl4. Optionally, compound 10 is also treated with a reducing reagent. Typical reducing reagents are of the form B(R30)3 such as BH3. Optionally reducing reagents of the form B(R30)3 are complexed with common solvents such as diethylether and dimethylsulfide. A wide range of borane reducing reagents are known and will not be described in detail here. For example Brown, H. C. xe2x80x9cBoranes in Organic Chemistryxe2x80x9d, (Cornell Univ. Press, Ithaca, N.Y., 1972) (Brown) provides a very large number of examples such as is found in Part Four, Selective Reductions, pages 209-251, Part Five, Hydroboration, pages 255-297, and Part Six, Organoboranes, pages 301-446.
In a typical embodiment, compound 10 is treated with a lewis acid in a nonerotic solvent. More typically, compound 10 is treated with a lewis acid and a reducing reagent in a nonerotic solvent.
In a typical embodiment, a solution of 10 in dichloromethane is cooled and treated with borane-methyl sulfide complex and trimethylsilyl trifluoromethanesulfonate. 10% Aqueous sodium bicarbonate solution is slowly added. The mixture is warmed to ambient temperature and stirred. The organic layer is filtered and concentrated in vacuo to leave compound 11. A detailed example of this embodiment is provided as Example 6 below.
In another example process of this embodiment compound 11 is of the formula: 
Another aspect of the present invention is directed to processes for the preparation of compounds of the formula: 
wherein:
R2, R4, R7, R20 and R21 are as defined above.
This process embodiment comprises reaction of a compound of the formula: 
with a reducing reagent.
The azide of compound 30 is reduced to form compound 31.
Typically the process comprises treating compound 30 with a reducing agent to form compound 31. More typically the process comprises treating compound 30 with hydrogen gas and a catalyst (such as platinum on carbon or Lindlar""s catalyst), or reducing reagents (typically a trisubstituted phosphine such as trialkyl (P(R25)3) or triaryl phosphine (PW3, e.g. triphenylphosphine). More typically still, the process comprises treating compound 30 with triphenylphosphine and a base to form compound 31.
Typically, compound 30 is disolved in a suitable polar, aprotic solvent such as anhydrous acetonitrile. A solution of anhydrous triphenylphosphine in a suitable solvent such as anhydrous tetrahydrofuran or a mixture of solvents is added dropwise. The mixture is heated at reflux then concentrated in vacuo to leave compound 5. A detailed example of this embodiment is provided as Example 9 below.
In another embodiment of this process compound 31 is of the formula: 
Another aspect of the present invention is directed to processes for. the preparation of compounds of the formula: 
wherein:
R2, R4, R5, R20 and R21 are as described above.
Y1 is a mono-, di- or unsubstituted amino group. Typically Y1 is of the formula xe2x80x94N(R30)2, a phthalimide or is a nitrogen containing heterocycle (defined above under W), more typically, Y1 is a phthalimide, more typically yet, a phthalimide salt.
This process embodiment comprises reaction of a compound of the formula: 
with an amine reagent. Typically, the amine reagent is of the formula HY1 or a salt of HY1, such as, by way of example, NH3 (McManns, et al., xe2x80x9cBull Soc. Chim. Francexe2x80x9d 850 (1947)), HY1 generally (Moussevon, M., et al., xe2x80x9cSynth. Commun.xe2x80x9d 3:177 (1973)) or phthalimide. (Gabriel, et al., xe2x80x9cBer.xe2x80x9d 20:2224 (1887) or Gibson, et al., xe2x80x9cAngew. Chem. Int.xe2x80x9d, 7:919-930 (1968)).
The process comprises treating compound 40 with the amine reagent to produce compound 32. More typically, compound 40 is treated with the amine reagent in a suitable polar a protic solvent (e.g. CH3CN, DMF or THF). Optionally compound 40 is treated with the amine reagent and a base. Typical details of this process embodiment can be found in March, xe2x80x9cAdvanced Organic Chemistryxe2x80x9d 4th. ed., pp 425-427.
In another embodiment of this process compound 41 is of the formula: 
Another aspect of the present invention is directed to processes for the preparation of compounds of the formula: 
wherein:
R2, R4, R20, R21 and Y1 are as described above;
This process embodiment comprises reaction of a compound of the formula: 
with an oxidizing reagent. A wide range of suitable oxidation reagents are common in the art and will not be detailed here. For example House, H. O. xe2x80x9cModern Synthetic Reactions, Second Editionxe2x80x9d, Chapter 5, pages 259-273, describes the selective oxidation of alcohols. Typical reagents include CrO3, Na2Cr2O7, KMnO4, PDC and PCC. Typical details of this process embodiment can be found in Larock, xe2x80x9cComprehensive Organic Transformationsxe2x80x9d, pp. 604-614; Corey et al., xe2x80x9cTetrahedron Lett.xe2x80x9d 31:2647-50 (1975); Ley et al., xe2x80x9cChem. Commonxe2x80x9d 1625 (1987); Sweon, et al., xe2x80x9cJ. Org. Chem.xe2x80x9d 43:2480-2 (1978); and Martin, et al., xe2x80x9cJ. Org. Chem.xe2x80x9d 48:4155-56 (1983). Solvents typically include inert polar solvents (e.g. CH2Cl2, toluene or CH3CN).
In another embodiment of this process compound 51 is of the formula: 
Another aspect of the present invention is directed to processes for the preparation of compounds of the formula: 
wherein:
R2, R4, R20, R21 and Y1 are as described above;
This process embodiment comprises reaction of a compound of the formula: 
with a base. Typically the base is a hindered amine or hindered alkoxide or the salts of either. More typically the base is of the formula NaOR25, KOR25 or NR253, more typically yet, DBN, DBU or diisopropyl ethyl amine.
In another embodiment of this process compound 61 is of the formula: 
Another aspect of the present invention is directed to processes for the preparation of compounds of the formula: 
wherein:
R2, R4, R7, R20 R21 and Y1 are as described above;
This process embodiment comprises reaction of a compound of the formula: 
with a reductive amination reagent. Typical details of and references to this process embodiment can be found in Larock, op. cit., pp. 421-425. Another typical description (NaCNBH3 method) is Borch, xe2x80x9cJ. Am. Chem. Soc.xe2x80x9d 93:2897-2904 (1971).
Schemes 1 and 2 depict embodiments of the invention. Detailed descriptions of the processes of Schemes 1 and 2 are provided in the Examples (below).
Additional individual process embodiments of the invention include any one or sequential combination of processes AA, AB, AC, AD, AE, AF, AG, AH, AI, AJ, or AK of Schemes 1 and 2. xe2x80x9cSequential combinationxe2x80x9d as used herein means more than one process wherein the individual processes are performed one after the other in the order shown. Isolation, separation, purification is optionally performed prior to any of the individual processes.